Aging in human subjects is accompanied by the inevitable development of cardiovascular and endothelial dysfunction, which, over time, especially as co-incident and superimposed aging-related disorders mount, leads to a heightened vulnerability to ischemia/reperfusion (I/R) stress. In response to the critique, we have developed and focused this project on two key components of aging cardiovasculature that prime the aged organism for amplified injury, both innately, and upon I/R. These studies are tightly coupled to Projects 1 &2 of this Program. First, basal degrees of inflammation increase in aged vasculature, particularly in aged endothelial cells (EC). Second, innate cardiomyocyte dysfunction develops in aging. Mitochondria become defective in cardiomyocytes as they age and increase generation of reactive oxygen species (ROS), thereby impairing ATP generation. Such fundamental injury phenomena promote conditions for enhanced cell death - especially in I/R. Thus, in both EC and cardiomyocytes retrieved from aged animals, identification of the precise signal transduction and transcriptional regulation mechanisms underlying these findings is essential in identifying novel targets to suppress adverse cardiovascular aging and diminish the amplified vulnerability to I/R stress. We will probe the hypothesis that increased activity of the polyol enzyme AR in aging drives mechanisms that enhance generation of AGE, thereby recruiting RAGE and consequent signal transduction in EC and cardiomyocytes;mechanisms which we predict are linked to cardiovascular dysfunction. We propose that when aged organisms are exposed to superimposed I/R stress in the heart, increased AR and AGE-RAGE signaling amplify production of inflammatory and stress mediators that exaggerate injury in the aged heart. In a manner highly synergistic with Projects 1&2 (intact heart), isolated EC and cardiomyocytes from aged animals will be used to probe the signal transduction and transcription factor mechanisms that regulate basal and I/R stress in the aged heart. Project 3 shares mouse/rat models with Projects 1 and 2. Project 3 will utilize all three Cores of the Program Project during all five years of the grant.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1)
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New York University
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Thiagarajan, Devi; Vedantham, Srinivasan; Ananthakrishnan, Radha et al. (2016) Mechanisms of transcription factor acetylation and consequences in hearts. Biochim Biophys Acta 1862:2221-2231
Thiagarajan, Devi; Ananthakrishnan, Radha; Zhang, Jinghua et al. (2016) Aldose Reductase Acts as a Selective Derepressor of PPAR? and the Retinoic Acid Receptor. Cell Rep 15:181-96
Zirpoli, Hylde; Abdillahi, Mariane; Quadri, Nosirudeen et al. (2015) Acute administration of n-3 rich triglyceride emulsions provides cardioprotection in murine models after ischemia-reperfusion. PLoS One 10:e0116274
Schmidt, Ann Marie (2015) Soluble RAGEs - Prospects for treating & tracking metabolic and inflammatory disease. Vascul Pharmacol 72:1-8
Gao, Minghui; Monian, Prashant; Quadri, Nosirudeen et al. (2015) Glutaminolysis and Transferrin Regulate Ferroptosis. Mol Cell 59:298-308
Schmidt, Ann Marie (2015) The growing problem of obesity: mechanisms, consequences, and therapeutic approaches. Arterioscler Thromb Vasc Biol 35:e19-23
Schmidt, Ann Marie (2014) Recent highlights of ATVB: diabetes mellitus. Arterioscler Thromb Vasc Biol 34:954-8
Vedantham, Srinivasan; Thiagarajan, Devi; Ananthakrishnan, Radha et al. (2014) Aldose reductase drives hyperacetylation of Egr-1 in hyperglycemia and consequent upregulation of proinflammatory and prothrombotic signals. Diabetes 63:761-74
Schmidt, Ann Marie (2014) Skin autofluorescence, 5-year mortality, and cardiovascular events in peripheral arterial disease: all that glitters is surely not gold. Arterioscler Thromb Vasc Biol 34:697-9
Bao, Li; Taskin, Eylem; Foster, Monique et al. (2013) Alterations in ventricular K(ATP) channel properties during aging. Aging Cell 12:167-76

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